why targetting just one oncogene may fail

[Lani]

or, looked at another way, why targetting the gene in early breast cancer may work so much better than later!

Cancer cells more likely to genetically mutate [Eureka News Service]
When cells become cancerous, they also become 100 times more likely to genetically mutate than regular cells, researchers have found. The findings may explain why cells in a tumor have so many genetic mutations, but could also be bad news for cancer treatments that target a particular gene controlling cancer malignancy.

The research was led by Dr. Lawrence Loeb, professor of pathology and biochemistry at the University of Washington School of Medicine in Seattle. Loeb will present his research Feb. 18 at the meeting of the American Association for the Advancement of Science in San Francisco.

Most types of cancer are believed to begin with a random genetic mutation that makes a normal cell go horribly awry. This is followed by mutations, which endow the cancer cells with properties allowing them to grow without normal controls to become a tumor. These mutated genes would be targets for chemotherapy.

But Loeb had another idea that he originally hatched many years ago - what if the cancer cells changed somehow, and became much more likely to mutate? These "mutator" cells would develop dangerous genetic mutations at a much faster rate than normal cells, which might account for the high number of mutations seen in tumor cells.

Since the technology of cancer genetics has dramatically improved, Loeb and his colleagues have only recently been able to test this hypothesis. They found that tumor tissue had random mutation rates up to 100 times higher than normal tissue from the same patient. The "mutator" hypothesis seems to be correct.

Now for the bad news: if cancer cells do indeed become "mutator" cells, traditional chemotherapy and other drugs may never be very effective against advanced tumors.

"This is very bad news, because it means that cancer cells in a tumor will have mutations that protect them from therapeutics," Loeb explained.

A chemotherapy drug may target a particular oncogene, which is a gene that affects the malignancy of a particular cell. But if cancer cells are mutator cells, a single tumor may have cells with many different types of oncogenes and drug-resistant genes. That chemotherapy drug may kill off some of the cancerous cells, but millions of other cells in the tumor will live on. To be effective, a chemotherapy treatment may have to target more than one oncogene - so-called combination chemotherapy.

Not all of the news is bad, though. Loeb believes this research may eventually help physicians determine the stage and malignancy of a tumor by testing the number of its mutations. The more mutations, the further along the tumor may be in its development to malignancy or metastasis.

Loeb's work may also lead to a discovery of why cancer cells are becoming mutator cells. If scientists understand what happens in a cancer cell that makes it become a mutator, they might be able to prevent that from happening in other cells, or slow down the mutation rate.

"The idea is that if you might normally get exposed to something in the environment at 20 years old that would give you cancer by age 55, then if we cut the mutation rate in half, you might not get cancer until age 90, and you may even die of something else before that," Loeb explained.

[AlaskaAngel]

A very obvious and unpleasant question is, do we know just how much the subsequent chemotherapy (and any sequential chemotherapies) itself might be contributing to the development of further "mutator" cells or an environment more likely to bring them on?

AlaskaAngel

[Hopeful]

AlaskaAngel,

This is one of my greatest concerns about chemotherapy and Her2. It seems to me highly mutagenic and I think often less is more. I have been intriguied by the descriptions of metronomic chemo, given low dose (below the toxic level) but sustained to knock out the cancer cells. The approach makes more sense to me from the git-go than giving toxic doses of these drugs with "breathers" in between for the healthy cells to recover and very possibly the cancer cells that are not knocked out in that treatment to figure out a way to survive the rest of them. Unfortunately, no one would do a clinical test of metronomic chemo in early stage bc patients, I guess it is counter-intuitive to the medical mind. If it was offered, this is something I would have seriously considered.

Hopeful

[gdpawel]

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

What needs to be done is to sort out what's the best profile in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, can they be identified? If one drug or another is working for some patients (not average populations) then obviously there are others out there who would also benefit.

What's good for the group (population) may not be good for the individual, affirms that in the tactic of using "fresh" biopsied cells to predict which cancer treatments will work best for the individual patient, these "smart" drugs have to get inside the cells in order to "target" anything.

So all the validation of this gene or that protein providing us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, if the targeted drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work. Each targeted drug is not for everybody. Even when the disease is the same type, different patients' tumors respond differently to the same agent or agents.

Once we are able to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then one, two, three or more targeted therapies, perhaps simultaneously, will be able to completely interrupt the flow of the cancer process.

It's not a case of throwing targeted drugs at the problem. It's knowing "what" targeted drugs work and "how" to use them in "individual" patients (not average populations). The problem is that few drugs work the way scientists think they do and few of them take the time to think through what it is they are using them for.

The headlong rush to develop tests to identify molecular predisposing mechanisms still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

http://weisenthalcancer.com/

http://www.rational-t.com/